(a) Field of the Invention
The present invention relates to a use of chemically-crosslinkable, poly(organophosphazene)s for biomaterials, chemically-crosslinkable, poly(organophosphazene)s with a physiologically active substance covalently-bonded thereto, a use thereof for biomaterials, and a process for preparing the same.
(b) Description of the Related Art
In chemically-crosslinked polymer hydrogels, chemical crosslinkings are either generated from a polymerization in a polymer set off by UV irradiation or produced from Michael-Addition between thiols and acrylate, acrylamide or vinyl sulfone group or from an enzyme, developing a network structure to change an aqueous polymer solution into a gel. (see, Biomaterials 29, 2153 (2008), Biomacromolecules 4, 713 (2003)). However, the chemically-crosslinked polymer hydrogels have limitations in their use for injectionable biomaterials since during their preparation, their gelation behavior and physical properties of the resulting gel are not easy to control and the formation of the gel requires a lot of time. (see, Biomaterials 24, 11 (2003), Biomaterials 26, 4495 (2005)).
In case of thermosensitive polymer hydrogels, the aqueous polymer solution maintains its liquid phase at a low temperature, but it changes into a gel with a increasing temperature. Such sol-gel behavior can be observed in a reversible manner. The thermosensitive polymer hydrogels can be simply injected into a required site without needing to perform a surgical operation and quickly form a gel of three dimensional structure at a body temperature, which makes their chance strong to be used for the injectionable biomaterials such as a delivery system for a physiologically active substance including drugs. (see, Nature, 388, 860 (1997), U.S. Pat. No. 6,201,072).
The present inventors have already reported as follows: poly(organophosphazene)s obtained by making a substitution on dichloro phosphazene linear polymers with amino acid esters and methoxy polyethylene glycols have the characteristics of the thermosensitive polymer with sol-gel behavior, being in an aqueous solution state below a certain temperature while turning into a three-dimensional gel above the certain temperature. Moreover, such thermosensitive poly(organophosphazene)s are slowly hydrolyzed in an aqueous solution. (see, Macromolecules 32, 2188 (1999), Macromolecules 32, 7820 (1999), Macromolecules 35, 3876 (2002), Korean Patent Nos. 259,367, and 315,630, U.S. Pat. No. 6,319,984).
However, these thermosensitive polymer hydrogels fail to have a sufficiently high level of solidity. This have limited their application in the biomaterials that are required to have satisfactory gel solidity, such as materials for plastic surgery and orthopedics including a filler, tissue engineering biomaterials including artificial cartilage, dental materials, materials for preventing stenosis including stent, adhesion barriers, and vasoocclusion materials. In addition, it takes a lot of time for these thermosensitive polymer hydrogels to form a gel after injection, which limit their use for injectionable biomaterials. Therefore, in order to make an improvement with respect to the foregoing problems, it is demanded to develop a biodegradable, thermosensitive poly(organophosphazene) with crosslinkings, the polymer not only exhibiting sol-gel behavior with a change in a temperature, but also being able to form crosslinkings, and possessing a higher level of gel solidity and controllable pore sizes.